Friday, February 25, 2005

A poignant question with a difficult answer

I received an anonymous comment/email from a patient with severe arthritis who is only able to tolerate the COX-2 inhibitors (which have apparently had a major impact on his or her quality of life).

This patient asks me whether I would wish to remove a patient's freedom to choose this class of medications even if he or she could consent to undertake any potential risks.

The question struck a chord in me both as a physician and as a person. I have therefore included the comment and an answer in the form of a brief essay.

Click here for complete essay.
I want to post a comment I received regarding my entry about the FDA's position on the COX-2 inhibitors:

"Medicine Man,

I am one of those who has been on Cox-2 inhibitors since they came out. I tried both Vioxx and Celebrex, and ended up on Vioxx at 50 mg for a few years, before I went to my Dr. and switched to Celebrex based on health concerns from published reports. This was several months before Merck pulled the drug.

I am now on 200 mg of Celebrex. The reason I'm not on any other NSAID is simple. I cannot take them, any of them that I've tried, without fairly immediate and severe gastric pain. And I have also been on Prilosec of another PPI for some time, and the gastric pain and other problems, such as water retention, occur anyway.

I have neck, back, knee, and ankle pain that diminishes on Cox-2's, and that makes it difficult to be active otherwise. Surely I ought to be allowed to make an informed decision to incur some additional cardiovascular risk, in exchange for the improvement in quality of life that Celebrex gives me? I also believe there is preliminary evidence that these drugs may be helpful for other conditions (e.g. prevention of colon cancer), so I'm willing to accept a risk that may not even exist in exchange for clear benefits. Do you disagree?"
This comment evoked some pretty strong feelings within me both as a person and as a physician. I see physical pain every day. In all of its varieties. Pain from cancer, pain from cardiovascular or lung disease, pain from trauma and the infinite spectrum of pain arising from rheumatic disease such as the different forms of arthritis.

Pain is the enemy. There have been patients of mine in pain, whose memories are indelibly burned into my psyche. Some of my greatest personal triumphs in medicine have been in the successful alleviating of pain, even in situations where the overall prognosis (e.g. due to cancer) is hopeless. Some of the worst feelings of impotence in my career have been in end-of-life situations where I was unable to relieve a patient's discomfort.

All of which makes this response to my entry all the more disturbing and poignant. Particularly when, with some qualifications, I do in fact disagree.

The issue here cuts at the heart of concern for the individual vs. concern for the public at large. This man or woman is clearly in pain and has clearly found a solution that works. Who am I and who is the government that would deny this fellow human his or her necessary treatment? The answer is someone who is also concerned about the public as well.

Prescription medications fall into an interesting class of consumer products. The end-user, the patient, is generally not sufficiently educated enough to determine which medications are appropriate and which aren't. That decision is usually made by another party, his healthcare provider (a term I hate but which includes doctors, nurse practitioners, physician assistants and others).

The patient's provider is constantly balancing risks and benefits of every therapeutic intervention in a way that requires considerable training and experience, at least to do it well. It's the relatively rare patient who is able to educate him or herself sufficiently to make informed decisions alone.

This being the case, society has decided at least in the U.S., that only "qualified" providers shall hold the hallowed prescription pads. On the balance, this works out fairly well and the public's welfare is well-served. The key is in finding a physician who is knowledgeable and who cares about you.

But what happens when a potentially beneficial drug (such as a COX-2 inhibitor) has serious deleterious effects? It comes down to the physician's ability to manage them safely and knowledgeably. Unfortunately, as a profession, there are times when we do this poorly. As an example I'd like to cite our experience with a drug I used to love prescribing called Propulsid manufactured by Janssen.

This was a very effective drug used to treat a common condition called gastroesophageal reflux disease (GERD). I found it to be very helpful in patients that failed every other medication. (By the way, when a patient doesn't respond to a treatment, we in the medical community are fond of saying that the patient failed treatment.)

Unfortunately, Propulsid was found to have a significant problem in that some otherwise healthy people died from taking it. It turns out that this drug is cleared from the body through some of the same metabolic pathways as other commonly used medications (erythromycin, some antidepressants, certain AIDS drugs and others). Because these pathways have only limited capacity, the concentration of Propulsid could achieve dangerous levels and cause lethal cardiac arrhythmias.

When this effect was noticed and studied after Propulsid had been introduced in the U.S., Janssen and the FDA formulated a plan for dealing with it. Janssen sent out a series of "Dear Doctor" letters to every physician in the U.S. explaining when not to use Propulsid. In addition they included a so-called "black box" warning in their package inserts. Black box warnings are terse, large print warnings surrounded with a big black box. They are essentially impossible to ignore by any physician that reads the insert which can otherwise be ten or more pages of dense, dry small print. Drug companies hate black box warnings because they can dramatically limit their ability to market medications. A black box warning from the point of view of the physician is like saying "DANGER, DANGER!".

One can imagine the reluctance Janssen had in undertaking these measures but the idea was that if doctors read the letters and the warnings, they should have no problem complying with them. Fewer adverse drug reactions would occur and the public safety would be protected. Unfortunately things didn't work out that way. The doctors weren't following the instructions despite the media concerns and the myriad of warnings. JAMA, a very important medical journal published a study, Smalley et al., demonstrating that the percentage of misuse of this medication was virtually unaffected by these measures.

Ultimately, Janssen removed Propulsid from the U.S. market on July 14, 2000. It is still available on a "limited use" basis but the paperwork and the liability issues of prescribing it would be daunting to most practitioners and very few patients are on it anymore.

So what does all this mean? To me it implies that we as physicians have failed our patients. If it could be shown that providers could comply with warnings of medications in a safe and appropriate manner, there wouldn't be any problem with the COX-2 inhibitors or other drugs with similar issues. As I've stated, most patients are unlikely to be sufficiently educated regarding risk/benefits. This is all the more so in light of the fact that physicians with seven or more years of "trade school" appear unable to assess risk/benefits either.

Which brings us back to the author of the comment above. Yes, you may be educated with regards to your particular clinical situation and, more apropos, with regards to your own body. Unfortunately, most patients and physicians aren't at least as far as the above-mentioned study and numerous studies like it demonstrate. When drugs with very important downsides are used to treat non-life-threatening diseases such as arthritis, the public interest must occasionally trump patient autonomy.

I did have a qualification though. When a drug has well-characterized risks and benefits due to good quantitative data, making the drug available on a limited-use basis may be appropriate. It seems clear that the author of that comment would be more than happy to sign an informed consent agreement. The problem arises when data regarding the risks of a drug is inadequate at present (as is the case for the COX-2 inhibitors). In that situation, giving truly informed consent is problematic.

For that reason I believe that for now, more data needs to be accumulated before these drugs can be safely "let loose" on the public. This is especially true given that the COX-2 inhibitors are a drug class with a massive patient base and that a misstep could have catastrophic consequences. It is also true that, for most patients, there are viable alternatives.

So to the author of the initial comment, believe me, I hear you.


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